Significance Hypoglycemia is major clinical problem in insulin-treated diabetes. Increased glucagon secretion is a primary defense against hypoglycemia, but glucagon responses to hypoglycemia are impaired in diabetes. The etiology of the impairment is poorly understood, but may involve a failure of the autonomic nervous system (ANS) to stimulate glucagon secretion since the ANS contributes to this response in several species. However, the role of the ANS in humans has been controversial. Objectives To investigate the importance of the ANS in hypoglycemia-induced glucagon secretion and the role of ANS deficits in impaired responses in a primate model of diabetes. Results We investigated the ANS contribution to hypoglycemia-induced glucagon secretion using two pharmacological approaches (blockade of ganglionic neurotransmission with trimethaphan or ANS receptor blockade) to impair the ANS inputs to the pancreas in conscious rhesus macaques. We found that the ANS has a major role in mediating the glucagon response during hypoglycemia of 2.0 mmol/L. These results were presented at the 31st Annual Meeting of the European Diabetes Association and a manuscript has now been published. Based on these results, we have conducted a study in human subjects and found a similar autonomic contribution to hypoglycemia-induced glucagon secretion in humans. A manuscript containing these results has been published. The nonhuman primate studies provided crucial background and methodological information for the human studies. In addition these results led to the writing of a review article on the implications of ANS regulation of glucagon for treatment of type-1 diabetes. Together these experiments were instrumental in allowing the P.I to obtain an NIH grant which began in April, 1997. Future Directions We are now starting new experiments to examine the autonomic regulation glucagon secretion during hypoglycemia and its impairment in monkeys with experimental diabetes. KEYWORDS hypoglycemia, glucagon, autonomic nervous system, diabetes